Transplant International

Growth arrest-specific gene 6 (Gas6) and its receptors Rse, Axl and Mer have recently been found to be involved in a rat model of chronic allograft nephropathy (CAN). Thus, in this study we investigated the function of Gas6 and its receptors in human renal allograft dysfunction. Expression of Gas6 and its receptors was detected by immunohistochemical staining. Gas6 and its receptors were widely expressed in glomeruli, tubules and vessels of renal allografts. Gas6 expression was detected in normal-functioning allografts and was increased in acute rejection (P<0.05), acute tubular necrosis (P<0.05) and CAN (P<0.01). Gas6 receptors were not upregulated in any of the allograft groups, except for the Axl receptor, which increased only in acute tubular necrosis (P<0.01). Gas6 expression was also found to correspond with the expression of α-smooth muscle actin, a general marker of CAN (r 2 =0.21, P<0.01). These findings suggest that Gas6, acting as a growth factor, is increased in the process of kidney allograft dysfunction and in CAN.

Various immunosuppressive regimens aim to reduce the incidence of acute rejection after liver transplantation. The efficacy of antithymocyte globulin (ATG) induction therapy and short-term effects on the cellular response have been demonstrated in several studies. Nevertheless, information about long-term effects of ATG therapy on cellular responses and frequency of complications is limited. Therefore, we analyzed the effect of ATG administration within a cyclosporine-based induction therapy, including azathioprine and prednisolone, on lymphocyte subsets and activation markers. We divided 35 liver transplant recipients into two groups according to their initial postoperative immunosuppression: a triple group without (n=15) and a quadruple group with ATG (n=20). The minimum observation time (flow cytometry analysis, clinical follow-up) was 2 years. Patients treated with ATG had persistently lower percentages of T cells for at least 2 years postoperatively (P<0.001). The CD4/CD8 ratios were lower in the quadruple group (P<0.005). The patients in the ATG group revealed a drop in CD25+ T cells within 2 years (P<0.05). However, the percentage of CD71+ and HLA-DR+ T cells was temporarily higher in patients with ATG treatment (P<0.05). Patients with ATG treatment showed persistently higher levels of CD8+/CD57+ double positive cells in the late postoperative phase (P<0.05). In contrast, no differences could be observed between the two groups for major parameters of clinical outcome (acute rejections, severe infections, patient survival). We conclude that ATG therapy induces long-lasting alterations in T-cell subset composition. However, no beneficial clinical effect could be confirmed after liver transplantation.

Pharmacokinetic profiles were obtained for 16 heart or lung recipients following the administration of identical doses of cyclosporin as oral solution and capsules on consecutive days. A comparison of pharmacokinetic parameters (AUC, Cmax, Cmin and tmax) showed that there were no significant differences between the two formulations except for the tmax, which was significantly longer for the capsules. The mean variation in day-to-day trough levels produced by the two different forms was 25.6%. A retrospective study was carried out of consecutive cyclosporin levels in patients at steady state on oral solution. The mean variation in day-to-day trough levels was 32.3%. This was not significantly different from the variation in consecutive trough levels seen in the oral solution/capsule comparison. This study shows that cyclosporin capsules can be substituted for oral solution without causing acute changes in cyclosporin blood levels, and that the pharmacokinetics of the two formulations are similar.

Ganciclovir (GCV) prophylaxis or pre-emptive therapy significantly reduce the rate of cytomegalovirus (CMV) disease and viremia, but increase the potential for emergence of ganciclovir-resistant CMV strains. The inhibitor concentration at 50% (IC50) of GCV from 156 CMV isolates from 59 renal or heart transplant recipients was calculated by means of a rapid phenotypic susceptibility assay. Twenty-seven strains were from 14 patients undergoing GCV therapy. The IC50 was higher in patients under the prophylaxis regimen. One CMV strain, from a heart transplant recipient, became GCV-resistant after 1 month of therapy (IC50=13.7 μmol/l). These data, together with clinical and virological markers, suggested that a switch to foscarnet was necessary, and good evolution was observed. Thus, assay of CMV susceptibility to GCV could be helpful in clinical management.

My personal experience with DO and BD pancreas transplantation confirms that the DO technique is a safe procedure associated with more frequent, but less serious, complications. However, because of the likelihood of vascular thrombosis, graft survival probability does not reach the same level as that achieved by the BD technique. With triple drug induction therapy, recipients of BD pancreatic grafts often experience severe rejection episodes requiring intense antirejection therapy. Subsequently, the compromised immune system increases the susceptibility of the recipients to life-threatening infections. However, improved prophylactic and therapeutic measures, such as quadruple immunosuppressive induction therapy, CMV prophylaxis, and effective antifungal drugs, are now available. Therefore, these complications may now be prevented or effectively treated in most cases. The BD technique provides methods for diagnosing early graft rejection, which is obviously of major importance in isolated pancreas transplantation. Nevertheless, the further development of markers for early graft rejection, as well as of immunosuppressive approaches, seems necessary in order to improve the results of isolated pancreas transplantation. When the pancreas is transplanted simultaneously with a kidney using the BD technique, the probability of survival for both grafts is excellent. The problems directly associated with BD may be solved by draining the pancreatic duct to the intestine, which may ultimately prove to be the method that should be given preference.

In the H-2-compatible donor-recipient combination (BALB/c→DBA/2), pretransplant donor-specific blood transfusion (DST) via the portal venous (PV) route significantly prolonged cardiac graft survival. DST via the intravenous (IV) route (systemic circulation) also showed a marked prolongation of heart tissue transplant survival in this model. In the H-2-incompatible combination (BALB/c→CBA/H), DST via the IV — but not via the PV — route resulted in accelerated graft rejection.

The care for patients having organ transplants has improved greatly. This improvement is due, in part, to the advances in knowledge gained through clinical trials. These trials are most useful when they address questions which are important (to patients, their families and their clinical care-givers), which are at their most rigorous statistically (by reducing bias and increasing precision), and which relate closely to the real world. Statisticians and clinicians need to work together to achieve these aims.